Document Detail

A Novel Acidic 11B-Hydroxysteroid Dehydrogenase Type 1 (11B-HSD1) Inhibitor with Reduced Acyl Glucuronide Liability: The Discovery of 4-[4-(2-Adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid (AZD8329).
MedLine Citation:
PMID:  23088558     Owner:  NLM     Status:  Publisher    
Inhibition of 11B-HSD1 is viewed as a potential target for the treatment of obesity and other elements of the metabolic syndrome. We report here the optimisation of a carboxylic acid class of inhibitors from AZD4017 (1) to the development candidate AZD8329 (27). A structural change from pyridine to pyrazole together with structural optimization led to an improved technical profile in terms of both solubility and pharmacokinetics. The extent of acyl glucuronidation was reduced through structural optimsation of both the carboxylic acid and amide substituents, coupled with a reduction in lipophilicity leading to an overall increase in metabolic stability.
James S Scott; Joanne Deschoolmeester; Elaine Kilgour; Rachel M Mayers; Martin J Packer; David Hargreaves; Stefan Gerhardt; Derek J Ogg; Amanda Rees; Nidhal Selmi; Andrew Stocker; John G Swales; Paul R O Whittamore
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-10-22
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  -     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-23     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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